The History of Psilocybin: From Ancient Ritual to the Modern Lab

The history of psilocybin is the longest and best documented of any psychedelic in medicine. That fact gets buried under a lot of vague language about ancient wisdom and sacred mushrooms. The real record is specific, and most of it can be dated to the year.

The mushrooms were used in Mesoamerican ritual for centuries. A New York banker brought them to the American public in 1957. A Swiss chemist isolated and named the active molecule in 1958. Harvard turned the research into a scandal, the federal government placed psilocybin in Schedule I in 1970, and the science went quiet for roughly thirty years before it came back.

I am a psychiatrist, and this history matters for making sense of the current hype. The clinical evidence, the phase 3 trials, and where the FDA stands in 2026 are covered in our review of psychedelics for mental health. This is about where the drug came from: what these mushrooms are, who identified them, why they were banned, and how they got back into research labs.

Psilocybin is a Schedule I controlled substance. It’s not legal in North Carolina outside an authorized research trial, and nothing here is medical advice or a way to obtain it.

What Psilocybin Actually Is

Psilocybin is a naturally occurring compound found in more than 200 species of mushrooms, most of them in the genus Psilocybe. On its own it does very little. The body converts it to psilocin, and psilocin is the molecule that acts on the brain. Chemists call psilocybin a prodrug for that reason. It’s the stable form you can put in a capsule, and it turns into the active form after you swallow it.

Psilocin works mainly by stimulating one type of serotonin receptor, the 5-HT2A receptor, which sits in large numbers on neurons in the outer layers of the cortex. That single mechanism accounts for most of what psilocybin does, from the changes in perception to the effects researchers are now studying in depression. David Nichols, the pharmacologist at the University of North Carolina who wrote the standard scientific review of these drugs, describes that 5-HT2A action as the shared basis for the whole class of classic psychedelics.

Psilocybin is not chemically addictive, and it does not cause the physical dependence that opioids or benzodiazepines do. It is also structurally close to serotonin itself, which is part of why a mushroom compound ended up mattering to psychiatry at all.

Teonanácatl: The Mushrooms Before the West Found Them

People in Mesoamerica were using psilocybin mushrooms for a very long time before any of this reached a laboratory. The Nahuatl-speaking peoples of central Mexico had a name for them: teonanácatl, usually translated as “flesh of the gods.” Spanish chroniclers in the sixteenth century, including the Franciscan friar Bernardino de Sahagún, recorded their ceremonial use and, predictably, tried to stamp it out.

The practice survived. It moved into the hills and continued quietly in Indigenous communities in Oaxaca and elsewhere for centuries. When Western researchers finally documented it in the twentieth century, the tradition was already ancient.

1957 and 1958: How Psilocybin Reached the Lab

The modern story starts with Robert Gordon Wasson, a vice president at J.P. Morgan and a serious amateur mycologist. In 1955, Wasson traveled to Huautla de Jiménez, in the Mexican state of Oaxaca, and took part in a nighttime mushroom ceremony led by a Mazatec curandera named María Sabina. On May 13, 1957, Wasson described the experience in Life magazine, in an article titled “Seeking the Magic Mushroom.” It reached millions of readers and put teonanácatl, the Mesoamerican mushrooms, in front of the Western public.

The chemistry came the next year, from Basel. Albert Hofmann, the Sandoz chemist who had first synthesized LSD in 1938, obtained samples of Psilocybe mexicana and isolated its active compound in 1958. He named it psilocybin, and he identified a second active molecule, psilocin. Two papers in the Swiss journal Experientia recorded the work that year: the isolation in March, with the mycologist Roger Heim who had classified the mushroom, and the full structure and synthesis in November. Sandoz then manufactured synthetic psilocybin in tablet form and supplied it to researchers under the trade name Indocybin.

Popular accounts routinely blur these into a single event. They are two separate things: Wasson’s 1957 magazine article and Hofmann’s 1958 chemistry. The mushrooms themselves predate both by centuries, used in ritual across Mesoamerica long before any European wrote down the word teonanácatl.

Hofmann’s synthesis turned psilocybin from an exotic botanical into a defined drug that researchers could dose by the milligram. That is what made the first clinical studies possible in the late 1950s and 1960s.

The CIA put $2,000 into Wasson’s 1956 expedition through a front. I tell that story in the CIA’s MKUltra experiments.

Harvard, Timothy Leary, and the Good Friday Experiment

In 1960, a Harvard psychologist named Timothy Leary tried psilocybin mushrooms on a trip to Mexico and came back convinced they could remake psychology. With his colleague Richard Alpert, he started the Harvard Psilocybin Project and began running studies with Sandoz-supplied psilocybin. Some of the early work was serious. The Concord Prison Experiment tested whether psilocybin sessions could reduce reoffending, and a graduate student named Walter Pahnke ran the study the project is still best known for.

On Good Friday in 1962, in a chapel at Boston University, Pahnke gave psilocybin or a placebo to twenty divinity students and measured whether the drug could produce a genuine mystical experience. Most of the students who received psilocybin reported one. The Marsh Chapel Experiment became a landmark, and a long-term follow-up decades later found that the participants still rated it among the spiritually significant events of their lives.

The research did not last. Leary and Alpert blurred the line between research and advocacy, dosing became casual, and Harvard dismissed both men in 1963. Psilocybin was now tied to the counterculture, and that association would shape the next decade more than any trial result.

1970: Schedule I and the Thirty-Year Freeze

When Congress passed the Controlled Substances Act in 1970, it sorted drugs into five schedules. Schedule I is the most restrictive category, reserved for drugs the law treats as having a high potential for abuse and no currently accepted medical use. Psilocybin went into Schedule I, alongside LSD, heroin, and cannabis, and it has stayed there ever since.

That classification did two things. It reflected a real political reaction to the excesses of the 1960s, and it made legitimate research almost impossible. A Schedule I license is difficult to obtain, the paperwork is heavy, and the funding mostly dried up. For most of three decades, serious clinical work on psilocybin nearly stopped.

As a forensic psychiatrist, this is where I would push back. The Schedule I decision was a legal and political judgment more than a settled scientific one, and the “no accepted medical use” language became partly self-fulfilling. Once the law made studies this hard to run, the absence of evidence was close to guaranteed, and that absence was then cited as the reason to keep the restriction in place.

The Comeback: How the Research Returned

The revival was slow and deliberate, and it grew out of academic psychiatry, a long way from the counterculture that had gotten the drug banned. In the late 1990s, Franz Vollenweider in Zurich began publishing careful human studies again. In 2006, Roland Griffiths and his team at Johns Hopkins published a rigorous, double-blind study showing that a single high dose of psilocybin could reliably produce a profound, personally meaningful experience under controlled conditions. That result reopened the field in the United States.

That study made psilocybin research respectable again, which the 1960s work never did. Over the next fifteen years, groups at Hopkins, NYU, Imperial College London, and elsewhere ran trials in depression, anxiety at the end of life, and addiction. By the early 2020s, psilocybin held a Breakthrough Therapy designation from the FDA and was moving through the phase 3 trials that will decide whether it becomes an approved medicine.

I’ve written separately about treatment-resistant depression and about what the current psychedelic evidence actually shows, including the phase 3 numbers, which are more modest than the headlines suggest. After a thirty-year gap, psilocybin is back in controlled clinical trials, which is the only setting that can answer whether it actually works.

Why It Matters to Psychiatry

Psilocybin quiets the default mode network, the set of connected regions most active when the mind is at rest and self-referential thought is running. Many researchers suspect that this temporary loosening of rigid, self-focused patterns is part of why the drug can shift entrenched depression, though that link remains a hypothesis and is not yet proven in humans.

There is also growing evidence, mostly from animal studies so far, that psilocybin promotes neuroplasticity, the brain’s ability to form new connections. If that holds up in humans, it would fit a larger shift in how psychiatry thinks about depression. The old chemical imbalance explanation hasn’t held up well, and models built around neuroplasticity and brain circuits have largely replaced it.

For the receptor-level account, from 5-HT2A to the default mode network to the neuroplasticity data, see how psilocybin works in the brain.

Where the Law Stands Now

Federally, the basic fact has not changed. Psilocybin remains a Schedule I drug, and it is not approved by the FDA for any medical use as of 2026. Possession is a federal crime, and the same is true in North Carolina, where psilocybin is a Schedule I substance under state law as well.

Two states have carved out narrow exceptions. Oregon, through Measure 109, and Colorado, through Proposition 122, created state-regulated programs for supervised adult use in licensed settings. These are non-medical programs confined to licensed service centers within each state. They are not medical prescriptions, and they have no legal effect in North Carolina. Both programs also exist in tension with the federal law that still classifies the drug as illegal, and Oregon’s has struggled financially since it opened.

For a patient in North Carolina, the practical situation is simple. There is no legal route to supervised psilocybin here outside an FDA-authorized research trial. If that changes, it will change because the FDA approves a psilocybin product and the DEA reschedules the drug, and both of those steps depend on the phase 3 results and the federal decisions that follow.

If you’re living with depression that hasn’t responded to standard treatment, there are evaluated, evidence-based options available in North Carolina today, none of them psilocybin. That’s the work I do with patients across the state. You can book a consultation to talk through what actually fits your situation.

Frequently Asked Questions

Who discovered psilocybin?

The Swiss chemist Albert Hofmann isolated and named psilocybin in 1958 at the Sandoz laboratories in Basel, working from the Mexican mushroom Psilocybe mexicana. Hofmann is the same chemist who first synthesized LSD two decades earlier. The mushrooms were used in Mesoamerican ritual for centuries before him, and the banker R. Gordon Wasson brought them to Western attention in a 1957 Life magazine article, the year before Hofmann’s chemistry.

Is psilocybin legal in North Carolina?

No. Psilocybin is a Schedule I controlled substance under both federal law and North Carolina law. There is no legal route to supervised or medical psilocybin in the state outside an FDA-authorized clinical trial. Oregon and Colorado have created state-regulated programs, but those do not extend to North Carolina and are not medical prescriptions.

What is the difference between psilocybin and psilocin?

Psilocybin is the compound in the mushroom, and it is largely inactive on its own. After you ingest it, the body strips off a phosphate group and converts it to psilocin, which is the molecule that actually acts on serotonin receptors in the brain. Psilocybin is the stable storage form, and psilocin is the active one, so scientists call psilocybin a prodrug.

How long have psilocybin mushrooms been used?

For centuries at least. Psilocybin mushrooms were used ceremonially by Indigenous peoples in Mesoamerica long before written history documented it, and Spanish chroniclers described the practice in the sixteenth century. The scientific study of psilocybin is much younger and dates only to the late 1950s.

Is psilocybin FDA-approved for depression?

Not as of 2026. Psilocybin is in late-stage phase 3 trials for treatment-resistant depression, but it is not an approved medicine and remains a Schedule I drug. For a current read on what those trials actually show, see our review of psychedelics for mental health.

This article is for educational purposes only and is not medical advice. Psilocybin is a Schedule I controlled substance and is not available or legal for medical use in North Carolina outside an FDA-authorized clinical trial. Nothing here should be read as encouragement to obtain or use it. If you are struggling with depression or thoughts of suicide, help is available now. Call or text 988 to reach the Suicide and Crisis Lifeline.

References

1. Hofmann A, Heim R, Brack A, Kobel H. Psilocybin, a psychotropic substance from the Mexican mushroom Psilocybe mexicana Heim. Experientia. 1958;14(3):107-109. PMID: 13537892.
2. Hofmann A, Frey A, Ott H, Petrzilka T, Troxler F. Elucidation of the structure and the synthesis of psilocybin. Experientia. 1958;14(11):397-399. PMID: 13609599.
3. Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl). 2006;187(3):268-283. PMID: 16826400.
4. Nichols DE. Psychedelics. Pharmacological Reviews. 2016;68(2):264-355. PMID: 26841800.
5. Wasson RG. Seeking the Magic Mushroom. Life Magazine. May 13, 1957. Historical source.
6. Pahnke WN. Drugs and Mysticism (the Good Friday / Marsh Chapel Experiment). Harvard University; 1963. Long-term follow-up: Doblin R. Journal of Transpersonal Psychology. 1991;23(1):1-28. Historical source.
7. U.S. Drug Enforcement Administration. Drug Scheduling, Controlled Substances Act. dea.gov.
8. Oregon Health Authority. Oregon Psilocybin Services (Measure 109). oregon.gov.